CD1D

Biological significance

CD1d-presented lipid antigens activate a special class of T cells, known as natural killer T (NKT) cells, through the interaction with the T-cell receptor present on NKT membranes. When activated, NKT cells rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and interleukin 4 production.

CD1d also regulates lipid transport to macrophages which express CD36 on their surfaces.

Nomenclature

CD1d is also known as R3G1

Ligands

Some of the known ligands for CD1d are:

• α-galactosylceramide (α-GalCer), a compound originally derived from the marine sponge Agelas mauritanius with no physiological role but great research utility.
• α-glucuronyl- and α-galacturonyl- ceramides, a family of compounds of microbial origin which can be found, for example, on the cell wall of Sphingomonas, a ubiquitous Gram-negative bacterium. The related β-D-glucopyranosylceramide is accumulated in antigen-presenting cells after infection, where it serves to activate invariant NKTs (iNKTs), a special kind of NKT.
• iGb3, a self antigen which has been implied in iNKT selection.
• HS44, a synthetic amino cyclitolic ceramide analogue which has less contact with the TCR, activating iNKTs in a more constrained way than α-GalCer (specially in relation to Th2 cytokines production) and thus being more interesting for therapeutic use.

Tetramers

CD1d tetramers are protein constructs composed of four CD1d molecules joined together and usually fluorescently labelled, used to identify NKT cells or other CD1d-reactive cells. In particular, type I NKT cells and some type II NKT cells are stained by them. A differentiation of these two types can be obtained in human by using an antibody against the TCR Vα24 chain, which is specific of type I NKT cells.

Although they are the most widely used of CD1d oligomers, sometimes CD1d dimers (two units) or pentamers (five units) are used instead.

In obesity and type 2 diabetes

In obesity, NKT cells exhibit both an inflammatory and anti-inflammatory function. On the one hand, they release IFN-γ, but on the other hand, they reduce inflammation via the production of IL-4 and -10.

Despite the anti-inflammatory cytokines released by NKT cells, the overall effect of CD1d and NKT cells is that of mediating the inflammation caused by diet-induced obesity. Adipocyte-specific CD1d knock-out mice, when fed a high-fat diet, are protected from obesity and exhibit reduced adipose tissue inflammation.

Obesity itself also decreases the expression of CD1d, and mice fed a high-fat diet showed reduced levels of CD1d expression in adipocytes after 16 weeks. These data suggest that differentiated adipocytes could act as antigen-presenting cells for adipose iNKT cells and that reduced expression of CD1d might be associated with iNKT cells that have been dysregulated following diet-induced obesity.

Research from 2004 showed that iNKT cell counts may be reduced in diabetes type II. Transgenic non-obese mice in which CD1d molecules were overexpressed under the control of the insulin promoter within the pancreatic islets exhibited restored function of NKT cells as immunoregulatory. Diabetes was prevented in these transgenic mice.

CD1d has been shown to play an important role in metabolic biological processes, such as retinol metabolism and steroid hormone biosynthesis process activation. There is research that suggests a connection between the impaired activity of CD1d and MASLD. One study showed that feeding CD1d knock-out mice a high-fat diet impaired lipid metabolism in the liver.

References

References

1. "P15813 (CD1D_HUMAN)". Uniprot.
2. (November 2022). "CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses". Nature Communications.
3. (January 2012). "C-Galactosylceramide: Synthesis and Immunology". Comptes Rendus. Chimie.
4. (2007). "The biology of NKT cells". Annual Review of Immunology.
5. (August 2006). "The immunological function of iGb3". Current Protein & Peptide Science.
6. (March 2012). "Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties". Journal of Immunology.
7. (2008). "The role of NKT cells in tumor immunity". Advances in Cancer Research.
8. (2018). "Role of Natural Killer T Cells in the Development of Obesity and Insulin Resistance: Insights From Recent Progress". Frontiers in Immunology.
9. (June 2016). "Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice". Scientific Reports.
10. (April 2017). "Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity". Diabetes.
11. (May 2004). "Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice". Journal of Immunology.
12. (2022-04-08). "Multi-Omics Characterizes the Effects and Mechanisms of CD1d in Nonalcoholic Fatty Liver Disease Development". Frontiers in Cell and Developmental Biology.